The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for medically inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations has not yet been determined.
Sun et al BMC Cancer (2020) 20:646 https://doi.org/10.1186/s12885-020-07122-7 RESEARCH ARTICLE Open Access Management of medically inoperable and tyrosine kinase inhibitor-naïve early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: a retrospective multi-institutional analysis Yuemei Sun1,2, Mengwan Wu3, Mingxiu Zhou3, Xing Luo3, Yan Guo3, Hansong Bai3, Zican Zhang1,2, Wei Tian1,3, Xiaoshan Wang1, Yifeng Bai1, Xueqiang Zhu1, Haixia Pan1, Ying Deng1, Honglin Hu1, Jianling Xia1, Xinbao Hao4, Liangfu Han5, Min Wei6, Yingyi Liu7 and Ming Zeng1,3* Abstract Background: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for medically inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations has not yet been determined In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI treatment alone and combined radiation and TKI treatment on the survival outcomes in this patient subgroup Methods: A total of 132 cases of medically inoperable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from centers Among these patients, 65 received combined radiation and EGFR-TKI therapy (R + TKI) (49.2%), while 67 received EGFR-TKI (50.8%) treatment alone All patients were followed until death Results: For the R + TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < 0.001) In terms of progression-free survival (PFS), the median PFS in these two treatment groups was 24 months and 14.7 months respectively (log-rank p < 0.001) Multivariate analysis showed that R + TKI was independently associated with improved OS (adjusted HR 0.420; 95% CI 0.287 to 0.614; p < 0.001) and PFS (adjusted HR 0.420; 95% CI 0.291 to 0.605; p < 0.001) compared to TKI alone Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients (Continued on next page) * Correspondence: miller2002@yahoo.com Cancer Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China Full list of author information is available at the end of the article © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data Sun et al BMC Cancer (2020) 20:646 Page of (Continued from previous page) Conclusions: Upfront radiation to primary sites with subsequent TKI treatment is a feasible option for patients with medically inoperable EGFR-mutant non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with those yielded by TKI treatment alone Keywords: EGFR, Inoperable, Lung adenocarcinoma, Radiation therapy, TKI Background Lung cancer remains the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide GLOBOCAN (2018) estimates that lung cancer accounts for approximately 18.4% of the total cancer deaths [1] NSCLC is the dominant type of lung cancer, in which 40% of patients need surgical resection for localized disease However, certain patients are medically inoperable or unwilling to receive dramatically invasive procedures Lung adenocarcinoma is one of the most common subtypes of NSCLC In recent decades, it was found that 10– 15% of Caucasian patients harbor epidermal growth factor receptor (EGFR) mutations [2, 3] In comparison, this rate can be as a high as 60% in patients from Eastern Asia [4] This group of patients has a higher likelihood of being treated with EGFR targeted therapies (typically EGFR tyrosine kinase inhibitors (TKIs) because of the high tolerance, overall response rate (ORR) and prolonged progression -free Survival (PFS) [5].In addition, in patients with brain metastasis, the use of TKIs might potentiate the effect of radiation therapy [6, 7] Historically, medically inoperable lung cancer patients have been treated with primary radiation therapy, stereotactic body radiotherapy (SBRT) for stage I/II and concurrent external beam radiotherapy (EBRT) with chemotherapy for stage III [8] The clinical value of the adjuvant use of TKIs in these patients has been gradually revealed Two previous retrospective studies explored the effect of TKI treatment on survival outcomes in patients with resected lung adenocarcinoma and EGFR mutations from the US [9, 10] Their findings suggested that in resected stage I-III lung adenocarcinoma, adjuvant TKI might significantly improve the disease-free survival (DFS) rate compared to patients who not receive adjuvant TKI [9, 10] This trend was confirmed by another recent retrospective study based on a Chinese patient database, which had a higher prevalence of EGFR mutation [11] More recently, one phase III trial evaluated the adjuvant use of gefitinib in patients with completely resected stage II-IIIA (N1-N2) EGFR-mutant NSCLC [12] Their data confirmed that compared to the adjuvant chemotherapy grounp, the adjuvant gefitinib group had superior DFS, reduced toxicity, and improved quality of life compared to the adjuvant chemotherapy group [12] These findings imply that EGFR-targeting therapy might have clinical value for treating early-stage EGFR- mutatnt patients However, the necessity of local radiation for this subgroup of patients is not certain Therefore, there has been enormous interest in testing the efficacy of local radiation in addition to EGFR-TKIs Although the radiation with TKI have been published [13], there are no randomized data available to study EGFR-TKI versus combined radiation and TKI In this study, we aimed to pool multi-institutional data and to compare the influence of EGFR-TKI alone with that of combined radiation and TKI on the survival outcomes in TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations Methods Inclusion and exclusion criteria After approval by the Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital Investigation Committee, patient information was gathered from five academic centers Patients who had medically inoperable stage I to III EGFR mutant lung adenocarcinoma between January 1, 2010, and December 31, 2011, were identified Diagnosis and staging of primary tumors were performed according to AJCC version The inclusion criteria were TKI-naïve patients with newly diagnosed stage I to III disease who refused either surgery or chemotherapy for clinical node-positive disease, or patients who could not tolerate surgery but had resectable N disease Patients who were treated with radiation followed by EGFR-TKI or with EGFR-TKI followed by radiation at primary site progression (named R + TKI) and patients who received only EGFR-TKI therapy (named as TKI alone) were included The exclusion criteria were as follows: patients who had prior EGFR-TKI use patient who had EGFR-TKI resistance mutations patients for whom EGFR-TKI treatment was not performed after radiotherapy patients who received chemotherapy or immunotherapy, or received thirdgeneration TKIs such as osimertinib for T790M mutation during TKI treatment patients with brain, visceral or bony metastases or patients who were missing covariable data or had an insufficient follow up time To lessen a potentially confounding variable, patients who received surgical resection or neoadjuvant chemo- or immunetherapy at the time of initial treatment were also excluded Radiation included stereotactic body radiation therapy (SBRT) or conventional external beam radiation Sun et al BMC Cancer (2020) 20:646 Page of therapy (EBRT) The SBRT dose ranged from 10 to 18 Gy in to fractions, while conventional EBRT ranged from 50 to 74 Gy in 25 to 35 fractions The site of radiotherapy was the primary lesion Tumor response was assessed using RECIST1.1, an evaluation criterion for the efficacy of solid tumors Follow-up after treatment ocuurred once every months in the first year, once every months in the second and third years, and once every year in the fourth and fifth years Log-rank testing was used to assess the differences between the curves OS was defined from the date of initial diagnosis until the date of death PFS was defined from the date of initial diagnosis until the date of recurrence of a prior irradiated primary site(s) or the development of a new lesion Using Cox proportional hazards analysis, univariable and multivariable variables were examined for the factors associated with OS and PFS A value of p < 0.05 was considered statistically significant Data extraction Results After applying the inclusion and exclusion criteria mentioned above, 132 patients from five centers were included in this study Among the patients, 65 patients received combined radiation and EGFR-TKI therapy (49.2%), while 67 patients received EGFR-TKI (50.8%) treatment alone All patients were followed until death Patient characteristics are given and compared in Table The age (mean ± SEM) before therapy for the R + TKI group and TKI alone group was 70.2 ± 1.12 and 70.88 ± 1.01 years respectively The R + TKI group included 13 stage I, 16 stage II and 36 stage III patients, while the TKI alone group included stage I, 12 stage II and 47 stage III patients (Table 1) The χ2 test did not reveal any significant differences between the The following variables were collected for subsequent analysis: age, gender, clinical stage, smoking history, EGFR mutation, clinical stages, type of RT delivered, name of the EGFR-TKI, and type of systemic therapy after progressing on EGFR-TKI treatment Systemic disease status was assessed by the presence or absence of brain, or visceral or bone metastases at the time of initial treatment The site of first progression after primary site radiation (SBRT or conventional) was identified The date of initial cancer diagnosis; clinical stage; RT treatments; systemic therapy treatments; distant metastases including intracranial; visceral or bony disease; most recent follow-up; and death were recorded Positron emission tomography-computed tomography (CT) and CT scans of the chest, abdomen, pelvis, and bone scan were reviewed to ascertain the clinical stage, and any uncertain lesions required biopsies to rule out metastases Pulmonary function tests (PFT) were performed before and after chest radiation to monitor the changes in lung function for all SBRT patients Mediastinal node disease was evaluated by combinating PET and contract CT, and suspicious nodes were biopsied by endobronchial ultrasound (EBUS) EGFR mutations were evaluated by polymerase chain reaction amplification through next-generation sequencing (NGS) techniques Exons 18 to 21 were analyzed for the following mutation; a deletion on exon 19 (E746-A750), or a point mutation on exon 21 (L858R) The stduy excluded ALK rearrangements, Rose1 mutations and rare mutations Tumor response was assessed using RECIST1.1, an evaluation criterion for the efficacy of solid tumors Follow-up after treatment was once every months in the first year, once every months in the second and third years, and once every year in the fourth and fifth years Statistical analysis Statistical analyses were conducted using SPSS 25.0 software (SPSS, Chicago, IL, USA) and GraphPad Prism 7.04 (GraphPad Inc., La Jolla, CA) Characteristics of patients (categorical variables) in the two groups were analyzed by the χ2 test with two-sided Fisher’s exact test Kaplan-Meier OS curves and PFS curves were generated Table Comparison of the clinicopathological parameters between the R + TKI and TKI alone groups Parameters Age (mean ± SEM) Treatment P value R + TKI (N = 65) TKI alone (N = 67) 70.2 ± 1.115 70.88 ± 1.008 0.65 0.73 Gender Female 28 27 Male 36 40 No data I 13 II 16 12 III 36 47 N0 18 18 N1/N2 47 49 exon 19 54 58 exon 20 exon 21 EBRT 61 SBRT Pathological stages 0.20 Nodal status 1.00 EGFR mutations 0.86 Radiation therapy EBRT External beam radiation therapy, SBRT Stereotactic body radiation therapy 0.99 Sun et al BMC Cancer (2020) 20:646 parameters, including age, gender, stage, nodal status, EGFR mutations and type of radiation therapy (p > 0.05) (Table 1) Comparison of the survival outcomes between the two therapeutic strategies For the R + TKI group, the median OS after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < 0.001; Fig 1a) The median PFS in these two treatment groups was 24 months and 14.7 months respectively (log-rank p < 0.001; Fig 1b) In the univariate analysis, advanced stages, EBRT and TKI alone were associated with significantly shorter OS Following the multivariate analysis R + TKI was independently associated with improved OS relative to TKI alone (adjusted HR 0.420; 95% CI 0.287 to 0.614; p < 0.001; Table 2), after controlling for other significant covariables In addition, multivariate analysis also showed that R + TKI was independently associated with improved PFS, compared to TKI alone (adjusted HR 0.420; 95% CI 0.291 to 0.605; p < 0.001; Table 3), after controlling for the significant covariables Controlled covariables included age gender, nodal status, stages, RT strategy Subgroup analyses To explore the potential variations of the survival benefits in patients with different clinicopathological parameters, we subdivided patients according to their pathological stages, T stages and nodal status Regardless of the therapeutic strategy, patients with higher pathological stages had a significantly shorter OS and PFS (log-rank p < 0.001; Fig 2a-b) In comparison, nodal positive cases had inferior OS at the margin level of significance (log-rank p = 0.064, Fig 2c) and significantly shorter PFS (log-rank p = 0.006, Fig 2d) Page of Those stage I patients who had the best survival outcomes did not have improved OS or PFS when they received combined radiation and TKI therapy (log-rank p = 0.38 and 0.50 respectively, Fig 3a and c) In stage II patients, although R + TKI did not improve OS (log-rank p = 0.14, Fig 3b), it substantially prolonged PFS (logrank p = 0.022, Fig 3e) In stage III patients who had the worst prognosis, R + TKI significantly improved both OS and PFS, compared to TKI alone (log-rank p < 0.001, Fig 3c and f) The median OS of the stage III R + TKI group was 30 months, which was similar to that of stage I and II patients who received TKI alone (30.5 months and 30.1 months respectively) In contrast, the median OS of stage III TKI alone was 27.8 months The median PFS of the stage III R + TKI group was 21.5 months, which was longer than that of stage I and II patients who had TKI alone (14.85 months and 15.35 months respectively) In comparison, the median PFS of stage III TKI alone was only 14 months When dividing the patients according to their T stages, R + TKI significantly improved both OS and RFS in the early T stage (T1/T2) (log-rank p = 0.017 and 0.004 respectively, Fig 4a-b) and the late T stage (T3/T4) (logrank p < 0.001, Fig 4c-d) cases In the subgroups divided by nodal status, R + TKI also significantly improved OS and PFS in nodal negative cases (log-rank p = 0.007 and 0.017 respectively, Fig 5a-b) and nodal positive cases (log-rank p = 0.007 and < 0.001 respectively, Fig 5c-d) cases Discussion To our knowledge, this is the first study in the literature to investigate the role of radiation before starting systemic therapy with the 1st generation of TKIs in patients with NSCLC harboring with EGFR-activating mutations For this cohort of patients, we demonstrated that TKI Fig Comparison of survival outcomes in patients who received R + TKI or TKI alone Kaplan-Meier OS (a) and PFS (b) curves were generated Patients included were separated into R + TKI (N = 65) and TKI-alone (N = 67) groups Sun et al BMC Cancer (2020) 20:646 Page of Table Univariate and multivariate analysis of OS Characteristics Univariate analyses P Age (Continuous) 0.688 Multivariate analyses HR 95% CI lower 95% CI upper 0.996 0.977 1.015 0.686 1.376 0.966 2.107 P HR 95% CI lower 95% CI upper Gender Male 1.000 Female 0.872 0.972 0.074 1.426 Nodal status N0 1.000 N1/N2 Stages I 1.000 II 0.110 1.592 0.900 2.818 III < 0.001 2.756 1.655 4.588 0.002 2.314 1.368 3.914 1.184 4.642 0.023 2.289 1.120 4.676 0.325 0.669 < 0.001 0.420 0.287 0.614 RT strategy SBRT 1.000 EBRT 0.015 2.344 Therapeutic strategy TKI alone R + TKI 1.000 < 0.001 0.466 HR Hazard ratio, CI Confidence interval, SBRT Stereotactic body radiation therapy, EBRT External beam radiation therapy, R + TKI Combined radiation and TKI alone is not as effective as upfront radiation therapy followed by TKI treatment in both PFS and OS in certain pathological stages In stage III patients, upfront RT followed by TKI significantly prolonged OS compared with the TKI alone group Upfront radiation is also associated with improved PFS in stage II/III patients, with fewer benefits in stage II than in stage III Moreover, the pathological parameters such as stages, performance status, age, gender, node metastases, and EGFR mutation exon location, were similar between the Table Univariate and multivariate analysis of PFS Characteristics Univariate Analyses P Age (Continuous) 0.355 Multivariate Analyses P HR 95% CI lower 95% CI upper 0.991 0.973 1.010 HR 0.748 1.502 1.171 2.767 0.283 95% CI lower 95% CI upper 0.741 0.428 1.282 Gender Male Female 1.000 0.743 1.060 Nodal status N0 N1/N2 1.000 0.007 1.800 Stages I 1.000 II 0.004 2.604 1.347 5.033 0.018 2.781 1.191 6.492 III < 0.001 3.408 1.918 6.053 0.002 3.474 1.599 7.548 1.572 6.355 0.005 2.779 1.353 5.710 0.326 0.662 < 0.001 0.420 0.291 0.605 RT strategy SBRT EBRT 1.000 0.001 3.160 Therapeutic strategy TKI alone R + TKI 1.000 < 0.001 0.465 Sun et al BMC Cancer (2020) 20:646 Page of Fig Comparison of survival outcomes in patients with different pathological stages and nodal status Kaplan-Meier OS (a and c) and PFS (b and d) curves were generated Patients were grouped according to their pathological stage (a-b) or nodal status (c-d) Fig Comparison of OS and RFS in patients in different pathological stages Kaplan-Meier OS (a-c) and PFS (d-f) curves were generated Patients were grouped according to their pathological stages Kaplan-Meier PFS curves were generated Sun et al BMC Cancer (2020) 20:646 Page of Fig Comparison of PFS in patients in early and late T stages Kaplan-Meier OS (a and c) and PFS (b and d) curves were generated Patients were separated into early T stages (T1/T2) (a-b) and late T stages (T3/T4) (c-d) groups Fig Comparison of OS and PFS in patients with different nodal statuses Kaplan-Meier OS (a and c) and PFS (b and d) curves were generated Patients were separated into nodal negative (a-b) and nodal positive (c-d) groups Sun et al BMC Cancer (2020) 20:646 R + TKI and TKI alone groups, suggesting that these two groups are comparable By performing multivariate analysis, we confirmed the prognostic significance of upfront radiation therapy followed by TKI treatment in both OS and PFS These findings suggest that the improved OS and PFS in the upfront RT group is not secondary to the pathological parameters between patient cohorts but is due to local therapeutic treatment at primary sites In randomized trials, few data have compared the effect of TKIs with or without radiotherapy for stage I to III subgroup disease Our data supported the assumption that stage I to III subgroup disease, local radiation therapy can improve survival by controlling disease progression In the stage I/II subgroup, SBRT provides much better local control, and the benefit from TKIs is less evident than that in more progressive stage III disease This could be a result of the high potential of radiation alone to cure early-stages disease compared with latestage disease Therefore, the trend toward increased OS by adding TKI to radiation is applicable to the fact that local therapy itself has less local controlling potential Large trials using standard first-line TKI treatment for the broad population of patients with metastatic NSCLC harboring EGFR mutations yielded a PFS between and 14 months without improving OS [5, 14–18] However, with the addition of local radiation to first-line TKIs for patients with EGFR-mutated metastatic NSCLC, both PFS and OS can be significantly improved Gomez et al conducted a randomized trial that compared local radiation versus maintenance treatment or observation for 49 patients with stage IV NSCLC with three or fewer metastases remaining after first-line systemic therapy [19] Their data showed that the median PFS was significantly improved with the use of consolidation therapy (11.9 versus 3.9 months, HR = 0.35,95% CI:0.18–0.66, p = 0.0054) Another randomized, phase II, open-label, multicenter study (SABR-COMET) demonstrated that aggressive local radiation doubled the DFS and also dramatically improved the OS Patients who received radiation/surgery experienced a median OS of 41.2 months vs 17.0 months among patients who received standard maintenance therapy/observation (p = 0.017) [20] In this study, we confirmed the role of upfront radiation in adding a survival benefit in medical inoperable stage I to III harboring EGFR mutant NSCLC patients compared with TKI alone In addition, the survival benefits were more evident in the late T stage or N stage Our study is unique in a number of ways when compared with similar, recently published research: (1) the radiation as local therapy depended the stage; (2) all patients had inoperable conditions; (3) no patient received the 2nd- or 3rd -generation TKIs, which are often used in daily practice to control the drug resistance from 1st- Page of generation TKIs after a year or so; (4) because of medical intolerance, no patients had received chemotherapy The combination of these features made this study cohort a unique subpopulation in the lung adenocarcinoma This study also has several limitations First, this was a retrospective study, with different providers of the 1stgeneration of TKIs were used; second, only a small proportion of patients received SBRT Therefore, a prospective study is needed Currently, studies investigating both consolidative RT after TKI (NCT03256981) and concurrent radiotherapy with TKI (NCT02893332) are ongoing Nonetheless, pending prospective validation, our results suggest that compared with TKI treatment alone, RT does significantly improve both PFS and OS in medically inoperable EGFR-mutant adenocarcinoma of the lung compared with TKI alone Although immunotherapy is accepted as a first-line therapy, a large percentage of patients harboring EGFR NSCLC who will receive TKIs as part of their treatment Therefore, the findings of this study will continue to be very relevant to patients with EGFR mutant NSCLC Conclusions In conclusion, upfront radiation to primary sites with subsequent TKI treatment is a feasible option for patients with mediclly inoperable EGFR-mutant NSCLC during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with those yielded by TKI treatment alone Abbreviations CT: Computed tomography; EGFR: Epidermal growth factor receptor; EBRT: External beam radiotherapy; EBUS: Endobronchial ultrasound; NSCL C: Non-small-cell lung carcinoma; NGS: Next-generation sequencing; OS: Overall survival; ORR: Overall response rate; PFS: Progression-free survival; PFT: Pulmonary function tests; SBRT: Stereotactic body radiotherapy; SABR: Stereotactic ablative radiation therapy; TKI: Tyrosine kinase inhibitor Acknowledgements We thank ZSJ for participating in the revision of the manuscript for reading the resubmitted manuscript for grammar and phrasing wording We also apperciate the patients and investigators of at the participating centers in China Authors’ contributions Both YS and MW (Mengwan, Wu) contributed equally to the article YSparticipated in the case collection, and in the drafting, and writing of the manuscript; MZ designed the study and performed the statistical analysis; MW (Mengwan, Wu) participated in the analysis and interpretation of the data; MZ (Mingxiu Zhou), XLand YG made useful comments and participated in revising the manuscript; HB, ZZ, WT, XW, YB, XZ, HP, YD, HH, JX, XH, LH, MW (Min Wei) and YL participated in the data acquisition All authors have read and approved the final version for publication Funding This study was funded by the a Research Grant from the Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital (No.30305031017P), the National Science and Technology Foundation (No.3035031263), and the Sichuan Science and Technology Office (No.3050410336) The funders had no roles in the study design, in collection, Sun et al BMC Cancer (2020) 20:646 analysis and interpretation of data, in the writing of the report, or decision to submit the article for publication Availability of data and materials The datasets and analyzed during the current study are available from the corresponding author on reasonable request Ethics approval and consent to participate The study was approved by the Ethics Committee of Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital Written informed consent was obtained from all patients to undergo radioterapy or targeted therapy Given that this is a retrospective study, we did not obtain written informed consent from any all patients to participate in this study All the above are agreed by the ethics committee Consent for publication Not applicable Competing interests The authors declare that they have no competing interests Author details Cancer Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China 2North Sichuan Medical College, Nanchong, Sichuan, China 3School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China Sino-America Cancer Center, Hainan Medical University, First Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China 5Cancer Center, BoaoEvergrande International Hospital, Qionghai, Haikou, Hainan, China Cancer Center, Ziyang People’s Hospital, Ziyang, Sichuan, China 7Dept of Radiation Oncology, Sichuan Friendship Hospital, Chengdu, Sichuan, China Received: 28 September 2019 Accepted: 30 June 2020 References Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018;68(6):1–31 Paez JG, Janne PA, Lee JC, et al EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy Science 2004;304(5676):1497– 500 Dogan S, Shen R, Ang DC, et al Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers Clin Cancer Res 2012;18(22):6169– 77 Li C, Fang R, Sun Y, et al Spectrum of oncogenic driver mutations in lung adenocarcinomas from east Asian never smokers PLoS One 2011;6(11): e28204 Maemondo M, Inoue A, Kobayashi K, et al Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR N Engl J Med 2010;362(25): 2380–8 Soon YY, Leong CN, Koh WY, Tham IW EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis Radiother Oncol 2015;114(2):167–72 Magnuson WJ, Lester-Coll NH, Wu AJ, et al Management of Brain Metastases in tyrosine kinase inhibitor-naive epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multiinstitutional analysis J Clin Oncol 2017;35(10):1070–7 Kang KH, Okoye CC, Patel RB, et al Complications from stereotactic body radiotherapy for lung cancer Cancers (Basel) 2015;7(2):981–1004 Janjigian YY, Park BJ, Zakowski MF, et al Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations J Thorac Oncol 2011;6(3): 569–75 10 D'Angelo SP, Janjigian YY, Ahye N, et al Distinct clinical course of EGFRmutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib J Thorac Oncol 2012;7(12): 1815–22 Page of 11 Lv C, An C, Feng Q, et al A retrospective study of stage I to IIIa lung adenocarcinoma after resection: what is the Optimal adjuvant modality for patients with an EGFR mutation? Clin Lung Cancer 2015;16(6):e173–81 12 Zhong WZ, Wang Q, Mao WM, et al Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase study Lancet Oncol 2018;19(1):139–48 13 Chang CC, Chi KH, Kao SJ, et al Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: a monoinstitutional experience Lung Cancer 2011;73(2):189–94 14 Zhou C, Wu YL, Chen G, et al Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802) Ann Oncol 2015;26(9):1877–83 15 Yang JC, Wu YL, Schuler M, et al Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-lung and LUX-lung 6): analysis of overall survival data from two randomised, phase trials Lancet Oncol 2015;16(2):141–51 16 Camidge DR, Pao W, Sequist LV Acquired resistance to TKIs in solid tumours: learning from lung cancer Nat Rev Clin Oncol 2014;11(8):473–81 17 Mok TS, Wu YL, Thongprasert S, et al Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma N Engl J Med 2009;361(10):947–57 18 Rosell R, Carcereny E, Gervais R, et al Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase trial Lancet Oncol 2012;13(3):239–46 19 Gomez DR, Blumenschein GR Jr, Lee JJ, et al Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after firstline systemic therapy: a multicentre, randomised, controlled, phase study Lancet Oncol 2016;17(12):1672–82 20 Palma DA, Haasbeek CJ, Rodrigues GB, et al Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABRCOMET): study protocol for a randomized phase II trial BMC Cancer 2012; 12:305 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations ... publication Availability of data and materials The datasets and analyzed during the current study are available from the corresponding author on reasonable request Ethics approval and consent to participate... PFS and OS in medically inoperable EGFR-mutant adenocarcinoma of the lung compared with TKI alone Although immunotherapy is accepted as a first-line therapy, a large percentage of patients harboring... development of a new lesion Using Cox proportional hazards analysis, univariable and multivariable variables were examined for the factors associated with OS and PFS A value of p < 0.05 was considered